SUMMARY Tuberculosis remains a major global public health threat. Although relatively effective drug regimens are available, treatment failure remains a major roadblock to tuberculosis control. This is in part due to a high incidence of drug-resistant Mycobacterium tuberculosis (Mtb) strains, as well as the phenomenon of bacterial persistence. Persisters represent a reservoir of latent infection, which may progress to active disease when host immunity is compromised (e.g., with HIV co-infection), and also potentially contribute to the emergence of further drug resistance. Mtb is able to subvert key innate immune defence mechanisms exerted by the host macrophage; it can dampen the immune response, subvert macrophage killing and create a protected niche within this host cell. In the proposed work, the capacity of engineered nanoparticles to favourably modulate the response of macrophage, through delivered immunomodulatory signals, and achieve death of intracellular Mtb, will be investigated. These unique nanoparticles mimic Mtb (i.e. bacteriomimetic) in selected aspects of size, shape and composition. The nanoparticles proposed here are lipid polymer hybrid nanoparticles and metal organic frameworks (spherical and rod shaped) incorporating mycolic acids and/or the fungal wall polysaccharide ?- glucan. Strong published and preliminary data demonstrates the capacity of the polymer nanoparticles to induce killing of virulent Mtb in macrophages. This killing is only evident in intracellular Mtb and is similar to that achieved using an antibiotic. Metal organic framework nanoparticles can be synthesized and coated with macrophage targeting materials. The hypothesis of the project is that bacteriomimetic, immunotherapeutic nanoparticles will be effective against all forms of Mtb (including drug-resistant and persister populations) through immune modulation. Specifically, the project has 3 aims: 1) Characterize a panel of bacteriomimetic immunotherapeutic NPs; 2) Investigate response of infected macrophages and intracellular bacteria to the panel of NPs; 3) Assess in vivo response to, and efficacy of, NPs in murine infection model. This project is at the cutting edge of nanotechnology and tuberculosis research, and will provide several exciting research capacity development opportunities for scientists from South Africa and Zimbabwe (through a partnership with an on-going NIH funded HIV Research Training Program). The multi-national research team will be led by 3 new investigators, with research teams from Stellenbosch University, South Africa, the University of the Western Cape (a historically disadvantaged institution in South Africa) and South Dakota State University in the USA, partnered to propose a novel immunotherapy approach for tuberculosis based on nanoparticle-based delivery systems. The team has expertise in nanoparticle formulation and characterisation, in vitro and in vivo infection models, and tuberculosis immunology. Our results will advance the development of nanoparticle-based, host-directed therapies for tuberculosis.